| The heterogeneous hydrogenation of F-nitrobenzene was studied in a slurry batch reactor. One of the reduced products, F-aminophenol, is a key intermediate for the manufacture of an Active Pharmaceutical Ingredient (API) in late-stage clinical trials. Catalysts play a vital role in the hydrogenation of nitroaromatics. Heterogeneous reactions can be limited by either diffusion or kinetic control, depending upon the catalyst used or the reaction conditions. Several catalysts were rapidly evaluated using a high-throughput screening technique from a diverse group of 48 catalysts available, to choose a single catalyst for this study. The selection criteria included the reactivity, selectivity and availability of the catalyst for scale-up in pilot facilities.;Heterogeneous hydrogenation reactions exhibit a complex kinetic behavior and require a careful reaction rate control, as they produce highly energetic intermediates, such as hydroxylamines, that pose a safety concern upon scale-up. In addition, the mechanism for the formation of the dehalogenated aniline byproducts in these reactions has not been clearly identified. Such impurities can pose a potential risk for batch failure in pharmaceutical products. A detailed kinetic model was developed, elucidating the dominant pathway for the desired reaction. It was found that the hydroxylamine formation step is a mass transfer limited process, whereas the hydrogenolysis of hydroxylamine is kinetically limited. The reaction rate and the maximum concentration of hydroxylamine were both dependent on mass transfer rates and reaction temperature. Similarly, it was found that formation of a des-F impurity was also a function of both the mass transfer rate, as well as the reaction temperature. Both the temperature and mass transfer rate information were critical in order to meet the safety requirements and the product specification for the des-F impurity. It is vital to scale such reactions from laboratory to pilot plant scale at a similar mass transfer rate of hydrogen gas. An experimental technique was developed to scale these reactions at a constant overall mass transfer coefficient. The experimental method also gave a direct measurement of hydrogen solubility in the solvent system, along with the mass transfer coefficient values.;The reactions were scaled up to pilot plant reactors by maintaining the same mass transfer coefficient kLa from the lab scale measured using a non-reactive methanol/hydrogen system. Although the reactions were scaled based on comparable kLa, the reaction rate was found to be much slower than that of the lab reaction. Upon investigation, it was found that the difference in rates was caused by the presence of a nitrogen headspace in the reactor, put in place for safety. Even though nitrogen is considered to be an innocuous substance, it resulted in catalyst inhibition. The catalyst was characterized by physi- and chemisorption techniques to understand the catalyst inhibition mechanism. Once the inhibition was well understood, then the pilot plant reactions were scaled up safely and successfully under a hydrogen atmosphere, producing good quality material required for clinical trials. |
